STAT-1 is activated by IL-4 and IL-13 in multiple cell types
Introduction
Interleukin-4 (IL-4) and the closely related cytokine interleukin-13 (IL-13) share many immune regulatory functions, including enhanced expression of MHC class II and CD23 (FcεRII) genes (Chomarat and Banchereau, 1998, Jiang et al., 2000, Zurawski and de Vries, 1994), Ig class switching to IgE and IgG4 (Nelms et al., 1999), increased expression of adhesion molecules (Bochner et al., 1995, Doucet et al., 1998) and modulation of pro-inflammatory cytokine/chemokine production (Bonecchi et al., 2000, Deckers et al., 1998). Most of the activities of IL-4 and IL-13 can be ascribed to the activation of Signal Transducer and Activator of Transcription-6 (STAT-6) (Takeda et al., 1996). More recent studies, however, indicate that involvement from other signaling molecules, such as IRS-1/2, PI3 kinase and tyrosine phosphatases SHP-1 and SHP-2, are also crucial (Chomarat and Banchereau, 1998, Haque et al., 1998, Imani et al., 1997, Jiang et al., 2000, Keegan et al., 1994, Nelms et al., 1999, Wang et al., 1993, Wright et al., 1997).
Different types of IL-4/IL-13 receptors have been characterized (Aman et al., 1996, Donaldson et al., 1998, Keegan et al., 1994, Murata et al., 1998, Nelms et al., 1999, Orchansky et al., 1997, Zhang et al., 1997). Whereas the IL-4Rα chain and the common γ (γC) chain constitute the type I receptor, which is utilized solely by IL-4 (Keegan et al., 1994, Nelms et al., 1999), IL-4Rα and IL-13Rα1 form the type II receptor, a receptor shared by both IL-4 and IL-13 (Aman et al., 1996, Hilton et al., 1996). It has been well established that both human T cells and murine B cells do not express IL-13Rα1, precluding a response to IL-13 (Chomarat and Banchereau, 1998). Another high-affinity IL-13 binding receptor, IL-13Rα2, has been cloned from both human and mice, but no signaling capacity has yet been demonstrated (Donaldson et al., 1998, Zhang et al., 1997).
Both IL-4 and IL-13 are key modulators of immune responses in the asthmatic lung. These two cytokines exert their functions by recruiting lymphocytes and professional inflammatory cells, such as eosinophils and macrophages (D’Ambrosio et al., 2001), which contribute to airways hyperresponsiveness and, eventually, to remodeling of pulmonary structure (Holgate et al., 2000, Wills-Karp, 1999). Recent data utilizing animal models of allergic asthma indicate that IL-13 plays a central role in disease independent of IL-4 (Grunig et al., 1998, Wills-Karp et al., 1998). In an effort to determine if this is due to differences in signaling pathways employed by IL-4 and IL-13, we examined STAT family member activation by both cytokines in four different airway cell types. While we found no differences in STAT activation in response to IL-4 or IL-13, our results clearly indicate that, in addition to STAT-6 activation, STAT-1 is activated in response to both of these cytokines.
Section snippets
Cells, cytokines and antibodies
Bronchial smooth muscle cell (BSMC), human microvascular endothelial cell (HMVEC), normal human bronchial epithelial (NHBE), normal human lung fibroblast (NHLF), small airway epithelial cell (SAEC), normal human dermal fibroblast (NHDF), human mammary epithelial cell (HMEC) and human umbilical vein endothelial cell (HUVEC) cells are primary human cell lines purchased from Clonetics (San Diego, CA). They were cultured according to the instructions provided by the vendor. BSMC, HMVEC, NHBE, NHLF,
Expression of IL-4/IL-13 receptor subunits in primary human airway tissue cells
We first used ribonuclease protection assay (RPA) to examine the expression of all known IL-4/IL-13 receptor complex subunits in five primary human airway tissue cells: bronchial smooth muscle cells, human microvascular endothelial cells, normal human bronchial epithelial cells, normal human lung fibroblasts and small airway epithelial cells. A375, a natural IL-13Rα2-expressing cell line, and testis RNA were included as controls. As shown in Fig. 1, mRNAs for IL-4Rα and IL-13Rα1, components of
Discussion
Increasing evidence indicates that IL-13 plays a potent and unique role in the pathogenesis observed in asthma, parasitic infections and other pathological conditions. IL-4 shares many functional properties with IL-13, presumably because they share a common receptor composed of IL-4Rα and IL-13Rα1. In this study, we analyzed the direct effects of IL-4 and IL-13 on signal transduction in primary airway tissue cell lines by examining the activation of STAT proteins.
The specific activation of
References (53)
- et al.
cDNA cloning and characterization of the human interleukin 13 receptor alpha chain
J. Biol. Chem.
(1996) - et al.
Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma
Am. J. Pathol.
(2002) - et al.
DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites
J. Biol. Chem.
(2001) - et al.
Protein-tyrosine phosphatase SHP-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction
J. Biol. Chem.
(1998) - et al.
Interleukin-4 (IL-4) induces phosphatidylinositol 3-kinase (p85) dephosphorylation. Implications for the role of SHP-1 in the IL-4-induced signals in human B cells
J. Biol. Chem.
(1997) - et al.
IL-4/IL-13 signaling beyond JAK/STAT
J. Allergy Clin. Immunol.
(2000) - et al.
An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth
Cell
(1994) - et al.
The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain
J. Biol. Chem.
(1998) - et al.
An interleukin (IL)-13 receptor lacking the cytoplasmic domain fails to transduce IL-13-induced signals and inhibits responses to IL-4
J. Biol. Chem.
(1997) - et al.
Interferon-gamma-induced factor binding to the interleukin-4-responsive element of CD23b promoter in human tonsillar mononuclear cells: role in transient up-regulation of the interleukin-4-induced CD23b mRNA
Mol. Immunol.
(1998)
Regulation of endothelial and mesothelial cell function by interleukin-13: selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production
Blood
Activation of phosphatidylinositol 3-kinase by interleukin-13. An inhibitory signal for inducible nitric-oxide synthase expression in epithelial cell line HT-29
J. Biol. Chem.
Identification, purification, and characterization of a soluble interleukin (IL)-13-binding protein. Evidence that it is distinct from the cloned Il-13 receptor and Il-4 receptor alpha-chains
J. Biol. Chem.
Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells
Immunol. Today
Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT)6-deficient mice
J. Exp. Med.
IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells
J. Immunol.
Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes
J. Immunol.
Lineage-specific activation of STAT3 by interferon-gamma in human neutrophils
J. Leukoc. Biol.
Interleukin-4 mediates cell growth inhibition through activation of Stat1
J. Biol. Chem.
Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation
J. Immunol.
Interleukin-4 and interleukin-13: their similarities and discrepancies
Int. Rev. Immunol.
T helper 1 cells and interferon gamma regulate allergic airway inflammation and mucus production
J. Exp. Med.
Chemokines and their receptors guiding T lymphocyte recruitment in lung inflammation
Am. J. Respir. Crit. Care Med.
GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression
J. Interferon Cytokine Res.
IL-4 and IL-13 augment cytokine- and CD40-induced RANTES production by human renal tubular epithelial cells in vitro
J. Am Soc. Nephrol.
The murine IL-13 receptor alpha 2: molecular cloning, characterization, and comparison with murine IL-13 receptor alpha 1
J. Immunol.
Cited by (43)
Npy transcription is regulated by noncanonical STAT3 signaling in hypothalamic neurons: Implication with lipotoxicity and obesity
2024, Molecular and Cellular EndocrinologyEngineered macrophages acting as a trigger to induce inflammation only in tumor tissues
2023, Journal of Controlled ReleaseProinflammatory Pathways in the Pathogenesis of Asthma
2019, Clinics in Chest MedicineCitation Excerpt :Signaling through IL-4Rα leads to activation and phosphorylation of the transcription factor signal transducer and activator of transcription 6 (STAT6), which when phosphorylated forms a homodimer that can translocate to the nucleus and bind to the GATA-3 promoter, leading to GATA-3 transcription.66,67 The IL-13R is expressed on airway smooth muscle cells, endothelial cells, fibroblasts, bronchial epithelial cells, and most leukocytes, including eosinophils, basophils, mast cells, and B lymphocytes.68–72 It is not expressed on Th1 or Th2 CD4 cells, but is expressed on CD4 Th17 cells.73–75
IL-13 in asthma and allergic disease: Asthma phenotypes and targeted therapies
2012, Journal of Allergy and Clinical ImmunologyCitation Excerpt :STAT6 is then phosphorylated and activated, resulting in translocation of STAT6 to the nucleus for binding to specific DNA elements on the promoter regions of downstream genes for initiation of transcription.22 Although STAT6 is the well-recognized primary mediator of IL-13– and IL-4–induced gene expression, studies of gene-deficient mice have revealed that other transcription factors, such as STAT1,23,24 STAT3,25 and early growth response 1,23,26 also mediate IL-13–induced functions. A third IL-13 receptor is the IL-13Rα2 subunit.
IL-4 receptor as a bridge between the immune system and muscle in experimental myasthenia gravis I. Up-regulation of muscle IL-15 by IL-4
2009, Clinical ImmunologyCitation Excerpt :In vitro studies described in the current report, suggest that optimal muscle IL-15 production may require increased expression of IL-4R, probably triggered by exposure to AChR antibody, thereby allowing more effective activation of muscle by IL-4. IL-15 has long been studied as a growth and differentiation factor in muscle [38–42]. IL-15 is also well known for its effects on cells of the immune system.
Dendritic cells dysfunction in tumour environment
2008, Cancer LettersCitation Excerpt :Previous data has shown that constitutive activation of STAT3 in tumour cells suppresses tumour production of pro-inflammatory mediators, such as TNF, IFN-α and chemokine ligand 5. Blocking of STAT3 activity in tumour cells using dominant negative STAT3 constructs was found to increase the expression of these pro-inflammatory cytokines and chemokines [96]. Parallel studies have determined that activation of STAT3 is not only important in tumour cells, for the production of tumour-derived factors able to inhibit DCs differentiation, but also responsible for the abnormal myeloid differentiation of hematopoietic pluripotent cells HPC [97].